5-androstene-17beta-amines and process



2,905,675 S-ANDROSTENE-IZB-AMINES- AND PROCESS- Fred Kagan and Robert D. Birkenmeyer, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo,

Mich., a corporation-of Delaware No Drawing. Application January 5, 1959 Serial No. 784,898'

18 Claims; (Cl; 260-397) This invention relates to 3B-halo-N,N-bis-(2-haloethyl)- androsten 17,8 amine and 33- halo N'- (2'- haloethyl)-5-androsten-17B-amine and is more particularly concerned with 3,B-chloro-N,N-bis-(2-chloroethyl)-5-a11- drosten 175 amine, 3,6 chloro- N' (-2- chloroethyD- 5 androsten- 17,B-- amine, 3/3 chloro N,N bis- (2- iodoethyl) 5 androsten 17B- amine, 3B chloro 1 (2 iodoethyl) 5 androsten 17B- amine, 3 5tbromo- N,N bis (2 bromoethyl) 5 androsten 17B- amine, 3B bromo N (2 bromoethyl') 5 androsten' 17B amine, 35 bromo N,N bis (-2 iodoethyl) -'S androsten-- 173- amine, iodoethyl) 5- androsten 17,8- amine, the intermediates 17,8 bis (-2- hydroxyethyl)amino-- 5 androsten 3B- 01 and l 7fl-(2-hydroxyethyl)amino-5-androsten 3-B-ol and a process for the production thereof; The newcompounds of this invention include not only the free amines listed above, butalso their pharmacologically acceptable mineral and organic acid'salts, for example, the sulfates, hydrochlorides, and acetates.

The new compounds and the process of the present invention are illustratively represented by the. following formulae:

forms such as pills, tablets; capsules, syrups or elixirs 3,8 bromo N (2- States Patent n Pa e e S nt. 2; 1 .9

for oral use, or in liquidf forms whichare adaptable to the natural and synthetic cortical steroid hormones for injectable product's, The process of the present invention comprises: treat; ing 17B-amino-5 androsten-3 B ol (I) with' an hydroxy ethylating agent such as ethylene oxide orethyleneichlor'o hydren to obtain a mixture of l'lfl bis-(2-hydroxyethyl) amino-5-androsten-3}8-ol and l7fl-(2-h'ydroxyethyl) no-5-androsten-3fl-ol, and treating the said hydroxyethyl aminosteroids (II), with a haIogenating'a'gent such as thionyl halide or phosphorusoxyhalide', wherein the halogen is of atomic weight between 35 and 80, inclusive, to obtain 35 halo N,N bis (2 haloethyl) 5- androf sten- 17 3' amine and 3,3 halo N (2 halojethyll' 5- androsten-l7,8-amine (III), wherein the halogen is? of; atomic weight between-35 and 80, inclusive; The iodo' compounds of the invention: namely, 3fl}chloro-N;N is (2 iodoethyl) 5 androsten 17B'- amine, 35'- chloro- N (2 iodoethyl) 5 an'drosten 175 amine, bromo N,N bis ('2'-, iodoethyl) 5 and-rosten' 1 73- amine, 318 bromo N (2 iodoethyl) 5 androsten} l 7fiamine, are obtained from the correspondingchlore ethyl or bromoethyl compounds, represented by Formula III, by metathetic reaction using a'n alkali meta'l i9 ,dfe such as sodium orpotassium iodide, preferably. inthe" presence of an inertsolventsuch as acetone; I

The starting compound ofthe presentinve n'tio'n isj17;3- amino-5-andro1steri-3B-ol [L. Ruzicka and- M. WL G bergrI-Ielv. Chim. Acta., 19, 107 (1936)]. In, ca y ng out the process of the present invention, 1754mm 5.-

agent, for example, ethylene oxide or ethylene clil 'foi, hyd'rin. In the preferred e'mbodimentof the' present 1 ii-.. vention the steroid is usually reacted With the" hyld'ro'xy ethylating agent in an inert solvent suchas benzene, toluene, xylene, cyclohexane and the like; at a tempera: ture between and 150'C., and underpressure tof'pre vent escape of the hydroxyethylating reagent. Excess hydroxyethylating agent (ethylene'oxide, ethylene chlorohydrin) may be used instead of an inert 'solvent-L The time ofreactionisusually betWeen-x8and 24-'hours after which the resulting crude mixture of l'lfi-bis-(Z-hydroxyethyl) amino-5-androsten-3fi-ol" is recovered by filtration or evaporation, and'washed with an organic hydrocarbon solvent such as petroleum ether, hexanes, or benzene. Pure 17fl-bis-(2-hydroxyethyl) amino-.5-androsten-3j3-ol is, obtained by recrystallizing' the crude mixture from, for example, acetone or methanol. 17 6'-(2-hydroxyethyl)- amino-S-androsten-BB-ol is obtained from the mother liquors by chromatography over Florisil (synthetic Image nesium silicate) followed by crystallization from, for ex? ample, acetone or methanol. For the purpose-ofobtaim ing the'final products itis'unnecessary to purify. the crude mixture of 2-hydroxyethylaminosteroids, which canbe used'directly in the next step. 7

The crude mixture of 17B-bis-(2-hydroxyethyl)amino- 5-androsten-3B-ol and 17 ;8-(2 hydroxyethyl)amino.-5 androsten-SB-ol is treated with a-suitable halogenating agent'wherein th'e'halogen is of atomic number between 17' and 35, inclusive; thionyl bromide, phosphorus oxychloride or phosphorus oxybromide. In the preferred embodiment of the present invention the steroid is usually reacted with the halogenating agent (thionyl chloride, phosphorus oxybromide or the like) in an inert solvent such-asbenzene, toluene or xylene, at atemperature between 25 and f C. Alternatively, instead of the inert solvent. The time of reaction is usually between 2 and 24 hours, at the end-of which time a precipitate of 3,9-halo-N-(2-haloethyD-j androstene 173-amine hydrohalide can be separated from the re; action mixture, as by filtration. The filtrate is evapfor example, thionyl chloride,

excess halogenating agent can be used 3 orated to give crude 318-halo-N,N-bis-(2-haloethyl)-5- androsten-17p-amine which can be purified by conventional means, for example, by crystallization from alcohol, acetone, acetone-water mixture, and the like.

Treating pure 17fi-bis-(2-hydroxyethyl)amino-S-androsten-3fi-ol or pure 17,8-(2-hydroxyethyl)amino-5- androsten-IlB-ol with a halogenating agent in the manner described above is productive of the corresponding 313- halo-N,N-bis-(2-haloethyl)-5androsten-17{i-amine or 3,8- halo-N-(Z-haloethyl)-5-androsten-17B-amine, wherein the halogen is of atomic weight between 35 and 80, inelusive.

The iodo compounds of the present invention are prepared from the corresponding chloro or bromo compounds by treatment with an alkali metal iodide, such as sodium or potassium iodide, preferably in an inert organic solvent such as acetone, acetic acid, methyl ethyl ltetone, and the like. An excess of the alkali metal iodide (3 to moles) is generally used. When the reaction mixture is heated at 50 to 70 for 10 to 30 hours, replacement of the chlorine or bromine in the haloethyl grouping is achieved. Under these conditions, 38- chloro-N,N-bis-(2-iodoethyl) -5-androsten-17;3-amine, 3 ,6- hloro-N-(Z-iodoethyl)-5-androsten-17B-amine, B S-bromo-N,N-bis-(2-iodoethyl)-5-androsten-l7p-amine, and 3pbromo-N-(Z-iodoethyl)-5-androsten-17B-amine are prepared from 3e-chloro-N,N-bis-(2-chloroethyl)-5-androsten-17B-amine, 3e-chloro-N-(Z-chloroethyl)-5-androsten-17B-amine, 35-bromo-N,N-bis-(2 bromoethyl) 5- androsten-l75-amine and 3B-bromo-N-(2-bromoethyl)-5- aindrosten-17B-amine, respectively. The product can be isolated, when the solvent is water miscible, by adding a large volume of water and separating the precipitated steroid by filtration or extraction with, for example, methylene chloride. Alternatively, the product may be recovered by evaporation of the solvent from the reaction mixture, or by chilling the reaction mixture to obtain the product as a crystalline precipitate.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 1 7B-bis-(2-hydr0xyethyl amino-S-androsten-Sfi-ol and l7fl-(2-hydroxyethyl) amin0-5-androsten-3fi-ol In a 100 ml. stainless steel autoclave was placed a reaction mixture of 2 g. of 17B-amino-5-androsten-3fl-ol EL. Ruzicka and M. W. Goldberg, Helv. Chim. Acta., 19, 107 (1936)], 20 ml. of benzene and 2 ml. of ethylene oxide. The reaction mixture was heated at 125 C. with stirring for 18 hours, giving a slurry which was washed onto a filter with benzene. The slurry was washed with petroleum ether and dried to give 2 g. of a crude mixture of 17fi-bis-(2-hydroxyethyl-amino-5-androsten-3,6-ol and 176-(2-hydroxyethyl)amino-5-androsten-3l3-ol having a melting point of 192 to 198 C. The crude mixture was recrystallized 4 times from acetone to give an analytical sample of l7B-bis-(2-hydroxyethyl)amino-5- androsten-3fi-ol having a melting point of 205 to 208 C. and the following analysis:

Analysis.Caloulated for C H N0 C, 73.16; H, 10.41; N, 3.71. Found: C, 73.04; H, 10.39; N, 3.82.

The acetone mother liquors from the crystallization of 17fi-bis-(2-hydroxyethyl)amino-S-androsten-Bfi-ol are combined and concentrated by evaporation to obtain a dry residue. The residue is dissolved in a one to one mixture of methylene chloride and Skellysolve B hexanes and placed on a column of Florisil synthetic magnesium silicate which is then developed with mixtures of acetone and Skellysolve B hexanes containing increasing proportions of acetone from 2 to 50%. The first main fraction, obtained by evaporation of the eluate, consists of l7B-bis-(2-hydroxyethyl)amino-S-androsten 3B ol; the second main fraction is 17l3-(2-hydroxyethyl)amino-5- audrosten 35-01.

EXAMPLE 2 3fi-chl0r0 N,N bis-(2 chloroethyl) 5-andr0sten-17flamine and 3j-3-chloro-N-(Z-chloroethyl)-5 androsten- 17,6-amine A reaction mixture consisting of 1 g. of a crude mixture of 17;.8-bis-(2-hydroxyethyl)amino-5-androsten-35-ol and 17/3-(2-hydroxyethyl)amino-5-androsten-3fi-ol, 7 ml. of thionyl chloride, and 40 m1. of dry benzene was heated at about 40 C. for 16 hours. At the end of the reaction period a benzene-insoluble precipitate was separated by filtration and crystallized from an acetonewater mixture to obtain 3 3-chloro-N-(2-chloroethyl)-5- androsten l7 3-amine hydrochloride having a melting point of 281 C. and the following analysis:

Analysis.Calculated for C H Cl N -HCl: C, 61.99; H, 8.42; N, 3.44; Cl, 26.14. Found: C, 61.96; H, 8.84; N, 3.44; Cl, 26.38.

Treating the above hydrochloride with one equivalent of sodium or potassium hydroxide in aqueous alcohol gave 3B-chloro-N-(2-chloroethyl)-5-androsten-l7fi-amine.

The filtrate remaining from the separation of the 3fi-chloro-N-(2-chloroethyl)-5-androsten-l7/3-amine hydrochloride was evaporated, giving about 1 g. of a light tan solid. The thus-obtained solid was recrystallized from a mixture of acetone and water and gave Zip-chloro- N,N-bis-(2-chloroethyl)-5-androsten-l7 3-amine having a melting point of 96 to 97 and the following analysis:

Analysis-Calculated for C H Cl N: C, 63.80; H, 8.38; Cl, 24.57. Found: C, 63.92; H, 8.39; Cl, 24.49.

EXAMPLE 3 3,8 bromo N,N-bis (2 bromoethyl)-5 androsten- Uri-amine and 3B-br0mo-N-(Z-bromoethyl)-5-andr0- sten-I 7 fl-amine In the same manner as described in Example 2, but substituting thionyl bromide for thionyl chloride as the reagent, treating a crude mixture of l7 8-bis-(2-hydroxyethyl)amino-5-androsten-3B-ol and l7 8-(2-hydroxyethyl) arnino-5-androsten-3fi-ol with thionyl bromide is productive of 3fl-bromo-N-(2-bromoethyl)-5-androsten-l7- amine and 3B-bromo-N,N-bis-(2-bromoethyl)-5-androsten-l7B-amine, which are isolated following the procedure of Example 2.

EXAMPLE 4 3 B-chloro-N ,N -bis-(2-iod0eth yl -5 -andr0sten-1 7B-amine A mixture of l g. of 3,8-chloro-N,N-bis-(2-chloroethyl)-5-androsten-l7B-arnine, 2.1 g. of sodium iodide and 50 ml. of acetone was heated under reflux for 24 hours, then was filtered While hot. The filtrate was cooled in an ice bath and gave a precipitate of 3i3-chloro-N,N-bis- (2-iodoethyl)-5-androsten-17fi-amine having a melting point of to C. After recrystallization from acetone, the compound melted at 133.8 to 135.6.

In the same manner as described in Example 4, treating 3B bromo N,N bis (2 bromoethyl) 5 androsten- 17,8-amine with sodium iodide in acetone is productive of 3p bromo N,N bis (2 iodoethyl) 5 androsten-17fl-amine.

EXAMPLE 5 3 B-ch loro-N Z-iodoethyl -5 -artdr0ste'n-1 75-amine In the same manner as given in Example 4, treating 35 chloro N (2 chloroethyl) 5 androsten l7,3 amine (from Example 2) with sodium iodide in acetone is productive of 3 3-ch1oro-N-(2-iodoethyl)-5-androsten- 17,8 amine. Similarly, treating 3Bbromo-N-(2-bromoethyl)-5-androsten-17,B-amine (from Example 3) with sodium iodide in acetone is productive of 3,8-bromo-N- (2-iodoethy1)-5-androsten-l718-amine.

EXAMPLE 6 3,3 chloro N,N bis (2 chloroethyl) 5 andrasten- 17fi-amine hydrochloride Treating a solution of 3fi-chloro-N,N,bis-(2-chloroethyl)-5-androsten-l7p-amine in ethanol with one equivaient of concentrated aqueous hydrochloric acid is productive of 3fi-chloro-N,N-bis-(2-chloroethyl)-5-androsten 17fi-amine hydrochloride, which can be isolated by evaporation of the solvent.

In the same manner as shown above, treating 3fi-chloro- N,N-bis-(2-chloroethyl)-5-androsten-17B-amine with sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, benzoic acid, or the like is productive of the corresponding acid addition salt.

EXAMPLE 7 3/8-br0m0-N,N-bis-(Z-iodoethyl) -5-androsten-1 7fl-aminehydrochloride Treating a solution of 3B-bromo-N,N-bis-(2-iodoethyl)-5-androsten-l7B-amine in ethanol with one equivalent of concentrated aqueous hydrochloric acid is productive of 3,8-bron1o-N,N-bis-(2-iodoethyl)-5-androsten- 17,8-amine hydrochloride, which can be isolated by evaporation of the solvent.

In the same manner as given above, treating 3 8-bromo- N,N-bis-(2-iodoethyD-S-androsten-17/3-amine with sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, benzoic acid, or the like is productive of the corresponding acid addition salt.

EXAMPLE 8 j'fl-chloro-N- (Z-chloroethyl) -5-androsten-1 7p-amine sulfate Treating a solution of 3,8-chloro-N-(2-chloroethyl)-5- androsten-175-amine in ethanol with one equivalent of aqueous sulfuric acid is productive of 3B-chloro- I- (Z-ehloroethyl)-5-androsten-17 3-amine sulfate which can be isolated by evaporation of the solvent.

In the same manner as shown above, treating 3,8-chloro- N-(2-chloroethyl)-5-androsten-17fi-amine with hydrobromic acid, phosphoric acid, acetic acid, benzoic acid, and the like is productive of the corresponding acid addition salt.

EXAMPLE 9 3 3-bromo-N- (2-i0d0ethyl) -5-andr0sten-17/3-amine hydrochloride Treating a solution of 3B-bromo-N-(2-iodoethyl)-5- androsten-17B-amine (from Example 7) in ethanol with one equivalent of concentrated aqueous hydrochloric acid is productive of 3p-bromo-N-(2-iodoethyl)-5-androsten- 17fi-a1nine hydrochloride, which can be isolated by evaporation of the solvent.

In the same manner as given above, treating 3 fi-bromo- N-(2-iodoethyl) -5-androsten-17fl-amine with sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, benzoic acid, or the like is productive of the corresponding acid addition salt.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art. The invention is therefore to be limited only by the scope of the appended claims.

We claim: 1. A compound of the formula fl-n N-(OHZGHZX). CH;

wherein X is a halogen of atomic weight between 35 and 6 127, inclusive, Y is selected from the group consisting of chlorine and bromine, and wherein n is a whole number from 1 to 2, inclusive, and the pharmacologically acceptable mineral acid and organic acid amine addition salts thereof.

2. 3fl-chloro-N,N-bis-(2-chloroethyl) 5 androstenl7fl-amine.

3. 3p-chloro-N,N-bis-(2-chlor0ethyl) 5 androsten- 17fi-amine hydrochloride.

4. 3,6-bromo-N,N-bis-(2-bromoethyl) 5 androstenl7fi-amine.

5. 3p-chloro-N,N-bis-(2-iodoethyl) 5 androsten-- amine.

6. 3/8-bromo-N,N-bis-(2 iodoethyl) 5 androsten- 17fi-amine.

7. 3,6-bromo-N,N-bis-(2 iodoethyl) 5 androsten- 17fi-amine hydrochloride.

8. 3 3-chloro-N-(2-chl0roethyl) 5 androsten-17pamine.

9. BB-chloro-N-(2-chloroethyl) 5 androsten 17B- amine hydrochloride.

10. 3,8-bromo-N-(2-bromoethyl) 5 androsten-1718- amine.

11. 3B-chloro-N-(2-iodoethyl) 5 androsten 17 8- amine.

12. 3,8-bromo-N-(2-iodoethyl) 5 androsten 17;?- amine.

13. 3 8-bromo-N-(2-iodoethyl) 5 androsten 17B- amine hydrochloride.

14. A compound of the formula wherein n is a whole number from 1 to 2, inclusive.

15. 175-bis-(2-hydroxyethyl)amino-5-androsten-3fl-ol. 16. 1713-( Z-hydroxyethyl) amino-5 -androsten-3 [3-01. 17. A process for the production of a compound of the formula i 2CHz Y 5 wherein X is a halogen of atomic weight between 35 and 127, inclusive, Y is selected from the group consisting of chlorine and bromine, and wherein n is a whole number from 1 to 2, inclusive, which comprises: reacting 1713- amino-5-androsten-3B-ol with an hydroxy-ethyla-ting agent to obtain a compound of the formula f zc r b wherein n is a whole number from 1 to 2, inclusive, and reacting the latter compound with a halogenating agent.

18. A process for the production of 3p-chloro-N,N-bis- (2-chloroethy1)-5-androsten-17fi-amine which comprises: reacting 17,8-amino-5-androsten-3fi-ol in an inert solvent with ethylene oxide to obtain 17B-bis-(2-hydroxyethyD- amino-5-androsten-3 8-ol and reacting the latter compound with thionyl chloride in an inert solvent.

References Cited in the file of this patent UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,905,675 September 22, 1959 Fred Kagan et al.

It is hereby certified that error appears in the printed specificationof the above Y numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 4: line 16, 0 1 C21H32C12N2'HC1 read. O21H33C12N2 HG1: line 66 for 17,8 amine. read -17 fi-emine.-; column 5 lines 7 0 to 74, the lower 1eft-l1and portion of the formula should read as shown below instead of as in the patent:

Signed and sealed this 12th day of April 1960.

Attest KARL H. AXLINE, ROBERT c. WATSON, Attestz'ng Oyfioer. Gammz'ssz'oner of Patents. 

1. A COMPOUND OF THE FORMULA 